{"gene":"IL17RA","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2008,"finding":"IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex; surface plasmon resonance showed IL-17A and IL-17F bind IL-17RC with comparable affinities but bind IL-17RA with different affinities; siRNA knockdown of IL-17RA or IL-17RC abolished heterodimer activity in bronchial epithelial cells.","method":"siRNA knockdown, surface plasmon resonance (SPR), functional cytokine assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SPR biophysical binding measurements combined with siRNA knockdown in primary cells, single lab but two orthogonal methods","pmids":["18684971"],"is_preprint":false},{"year":2008,"finding":"IL-25 (IL-17E)-mediated activities require both IL-17RB and IL-17RA; splenocytes from IL-17RA KO mice failed to produce IL-5 or IL-13 in response to IL-25, and IL-17RA KO mice failed to respond to intranasal IL-25; blocking anti-IL-17RA mAb prevented IL-25 activity in human cells.","method":"Knockout mouse model, antagonistic antibody blockade, in vitro cytokine assay, in vivo pulmonary inflammation model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody blockade replicated both in vivo and in vitro, multiple orthogonal methods","pmids":["18768888"],"is_preprint":false},{"year":2010,"finding":"IL-17RA signaling requires an extended SEFIR domain (termed SEFIR+TILL) beyond the previously defined SEFIR motif for downstream signaling; Act1 recruitment alone is not sufficient for signaling, but TRAF6 ubiquitination correlates tightly with functional receptors; deletion of the CC' loop (not the BB' loop) from IL-17RA abolished Act1-IL-17RA interaction.","method":"Structure-function mutagenesis, receptor deletion constructs, functional reporter assays, ubiquitination assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with multiple deletion constructs and functional readouts in a single rigorous study","pmids":["20729198"],"is_preprint":false},{"year":2011,"finding":"The CC' loop of the SEFIR domain of IL-17RA is required for Act1 binding; SPR showed a CC' loop-based peptide directly binds IL-17RA; a cell-permeable CC' loop decoy peptide inhibited IL-17- and IL-25-mediated signaling in vitro and pulmonary inflammation in vivo.","method":"Surface plasmon resonance, deletion mutagenesis, cell-permeable decoy peptide in vitro and in vivo","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SPR binding assay plus mutagenesis plus in vivo functional validation, single lab with multiple orthogonal methods","pmids":["22045852"],"is_preprint":false},{"year":2010,"finding":"Both IL-17RA and IL-17RC are required for IL-17A- and IL-17F-induced NF-κB and MAPK (ERK, p38, JNK) activation and IL-6/IL-8/CCL20 secretion in human rheumatoid synoviocytes; siRNA silencing of either receptor nearly abolished IL-6 expression mediated by IL-17A.","method":"siRNA knockdown, MAPK western blotting, ELISA, microarray","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple downstream readouts, consistent with earlier findings in same cell type","pmids":["21109515"],"is_preprint":false},{"year":2007,"finding":"Both IL-17RA and IL-17RC are required for IL-17A-mediated activation of ERK, p38, JNK, AP-1, and p65 NF-κB in gastric adenocarcinoma cells; siRNA knockdown of either receptor nearly abolished IL-17A-induced c-Jun and p65 activation.","method":"siRNA knockdown, MAPK western blotting, transcription factor binding assay (TransAM), ELISA","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA with multiple downstream signaling readouts, single lab","pmids":["17644350"],"is_preprint":false},{"year":2008,"finding":"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine (CXCL1, CXCL5, CXCL6) expression in synoviocytes; siRNA silencing of either receptor reduced IL-17A-induced IL-6, IL-8, and CCL-20 secretion.","method":"siRNA knockdown, ELISA, microarray","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA plus microarray in primary human synoviocytes, single lab","pmids":["18097068"],"is_preprint":false},{"year":2018,"finding":"RKIP directly interacts with IL-17RA and Act1 to promote formation of the IL-17R-Act1 complex, resulting in enhanced MAPK and NF-κB activation and downstream cytokine production; RKIP deficiency in mice ameliorated EAE symptoms and reduced IL-17R-mediated proinflammatory responses.","method":"Co-immunoprecipitation, adoptive T cell transfer, KO mouse model, NF-κB/MAPK reporter assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying novel binding partner plus in vivo KO rescue, single lab","pmids":["29674348"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F revealed that IL-17RC forms a symmetrical 2:1 complex with IL-17F, competing with IL-17RA for cytokine binding; biophysical studies showed IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent signaling is possible.","method":"X-ray crystallography, biophysical binding assays (SPR/ITC)","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biophysical validation, reveals unexpected stoichiometry of the IL-17RC:IL-17F complex","pmids":["32187518"],"is_preprint":false},{"year":2022,"finding":"IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization; crystal structure of the extracellular domains of IL-17RA and IL-17RC in complex with IL-17A revealed a 2:2:2 hexameric signaling assembly; dimerization-defective IL-17RA mutants showed reduced IL-36γ and CXCL1 mRNA induction in human keratinocytes.","method":"X-ray crystallography, biophysical assays, mutagenesis, functional mRNA expression assay in keratinocytes","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional validation, multiple orthogonal methods in a single study","pmids":["36260993"],"is_preprint":false},{"year":2017,"finding":"Cyanidin specifically binds to an IL-17A binding site within IL-17RA (structure-based identification) and inhibits the IL-17A/IL-17RA interaction; this blocked IL-17A-induced skin hyperplasia and attenuated TH17-driven airway hyperreactivity in mice.","method":"Structure-based virtual screening, binding assays, in vivo murine models of psoriasis and asthma","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural modeling plus in vivo functional validation, mechanism confirmed by pharmacological inhibition","pmids":["28223414"],"is_preprint":false},{"year":2016,"finding":"A 15-residue phage-display-derived peptide (HAP) binds IL-17A and blocks IL-17A/IL-17RA interaction; crystal structure revealed two HAP molecules bind one IL-17A dimer symmetrically with the C-terminal helix directly blocking the IL-17RA binding region of IL-17A.","method":"Phage display, saturation mutagenesis, X-ray crystallography, primary human cell functional assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation in primary cells, multiple orthogonal methods","pmids":["27184415"],"is_preprint":false},{"year":2019,"finding":"IL-17A/IL-17RA signaling promotes fatty acid uptake in ovarian cancer cells via the IL-17RA/p-STAT3/FABP4 axis; IL-17RA was required for IL-17A-induced STAT3 phosphorylation and FABP4 upregulation, promoting cellular palmitic acid uptake.","method":"In vitro cytokine stimulation, Western blotting, IL-17A-deficient mouse orthotopic model, siRNA knockdown","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IL-17A-deficient mouse model plus in vitro mechanistic pathway delineation, single lab","pmids":["31802182"],"is_preprint":false},{"year":2011,"finding":"IL-17RA is required for CCL2 expression and MMP12 induction in response to cigarette smoke; IL-17RA-/- mice failed to develop emphysema after 6 months of cigarette smoke exposure, establishing IL-17RA signaling as necessary for smoke-induced COPD pathology.","method":"IL-17RA knockout mouse model, qPCR for CCL2 and MMP12, histological assessment of emphysema","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with specific molecular and histological readouts over 6-month exposure period","pmids":["21647421"],"is_preprint":false},{"year":2009,"finding":"IL-17RA signaling is required for neutrophil migration and myeloperoxidase increases in the lung after influenza infection; IL-17RA-/- mice showed reduced oxidized phospholipids and were protected from acute lung injury, but IL-17RA was dispensable for CD8+ T cell recruitment and viral clearance.","method":"IL-17RA knockout mouse model, flow cytometry, MPO assay, viral clearance assay, lipid oxidation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts distinguishing required vs. dispensable functions","pmids":["19783685"],"is_preprint":false},{"year":2013,"finding":"IL-17RA is required for optimal localization of follicular Th (TFH) cells in the germinal center light zone; IL-17 signaling upregulates RGS16 in TFH cells to promote TFH-B cell conjugate formation; IL-17RA deficiency in BXD2 mice abrogated autoantibody-forming B cell generation without affecting total TFH numbers.","method":"IL-17RA knockout mouse (BXD2-Il17ra-/-), adenoviral IL-17R:Fc blockade, immunofluorescence, in vitro conjugate formation assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus acute blockade, mechanistic link to RGS16 identified, single lab","pmids":["23858031"],"is_preprint":false},{"year":2022,"finding":"IL-17RA signaling in Lgr5+ intestinal stem cells induces ATOH1 transcription factor expression to promote secretory epithelial cell lineage commitment (Paneth, tuft, goblet, enteroendocrine cells); conditional deletion models showed IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury; IL-17A stimulation of human intestinal organoids rescued secretory cell differentiation.","method":"Conditional knockout mouse models, human intestinal organoids, lineage tracing, immunofluorescence","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional deletion models plus human organoid validation, replicated across cell types and species","pmids":["35081371"],"is_preprint":false},{"year":2019,"finding":"IL-17A promotes airway smooth muscle contraction by recruiting Rab35 (via DennD1C GEF) to the IL-17R/Act1 complex, activating PKCα and phosphorylating fascin at Ser39, enabling F-actin/myosin stress fiber formation; cell-type-specific deletion of IL-17R or Act1 in airway smooth muscle cells confirmed direct role.","method":"Cell-type-specific conditional KO, co-immunoprecipitation, Rab35 knockdown, PKCα inhibitor, contraction assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — conditional KO plus co-IP plus specific pharmacological inhibition with direct contractility readout","pmids":["30683702"],"is_preprint":false},{"year":2022,"finding":"FTO (a m6A demethylase) suppresses m6A mRNA methylation of IL-17RA, leading to increased IL-17RA expression; knockdown and overexpression of FTO in vitro and in vivo demonstrated FTO as the primary m6A modulator of IL-17RA, and increased IL-17RA promoted chronic hepatic inflammation.","method":"MeRIP-seq, FTO knockdown/overexpression, murine NAFLD/liver injury models, Western blotting","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus functional KD/OE with in vivo validation, single lab","pmids":["36172147"],"is_preprint":false},{"year":2013,"finding":"A soluble isoform of human IL-17RA is generated by alternative splicing that removes exon 11 encoding the transmembrane domain; RT-PCR confirmed this variant in multiple human tissues and the secreted protein was detected in culture media by Western blotting.","method":"RT-PCR, Western blotting of conditioned media","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal detection methods (RT-PCR and Western blot) for a novel isoform, single lab","pmids":["24084331"],"is_preprint":false},{"year":2019,"finding":"IL-17RA signaling in intestinal epithelial cells regulates microbial composition and constrains translocation of TLR9 ligands (CpG DNA); intestinal epithelium-specific IL-17RA deletion caused microbiome dysbiosis, increased CpG DNA translocation driving hepatic IL-18 production, and exacerbated immune-driven hepatitis.","method":"Intestinal epithelium-specific IL-17RA conditional KO mouse, 16S microbiome sequencing, hepatitis model, cytokine measurement","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with mechanistic chain from microbiome dysbiosis to IL-18 to hepatitis, multiple readouts","pmids":["31747600"],"is_preprint":false},{"year":2017,"finding":"IL-17 signaling in fibroblasts requires IL-17RA/STAT3 axis to induce SHP-2, Cyr61, IL-23, GM-CSF and RANKL expression in rheumatoid arthritis fibroblast-like synoviocytes; siRNA knockdown of IL-17RA reversed IL-17-induced RANKL expression and osteoclastogenic potential.","method":"siRNA knockdown, STAT3 inhibitor, co-culture osteoclastogenesis assay, Western blotting","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA plus pathway inhibitor plus functional osteoclastogenesis assay, single lab","pmids":["28898718"],"is_preprint":false},{"year":2018,"finding":"IL-17RA/Act1 signaling is required for IL-17R-induced lung immunity against Klebsiella; conditional deletion showed IL-17R signaling specifically in fibroblasts is required for lung-specific protective immunity (not systemic antibody-mediated protection) in a mucosal vaccine model.","method":"Cell-type-specific conditional IL-17R KO mouse, adoptive transfer, mucosal vaccine model, bacterial challenge","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO isolating fibroblast-specific function of IL-17R, single lab","pmids":["34516780"],"is_preprint":false},{"year":2019,"finding":"IL-17RA signaling in non-hematopoietic cells controls CXCL-1 and CXCL-5 production to recruit neutrophils to the lung during the adaptive immune response to mycobacteria; CXCL-1 and CXCL-5 instillation reconstituted neutrophil recruitment in IL-17RA-/- mice.","method":"IL-17RA KO mouse, bone marrow transplantation, cytokine instillation rescue experiment, flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO plus rescue experiment identifying IL-17RA in non-hematopoietic cells as key source, single lab","pmids":["26871571"],"is_preprint":false},{"year":2024,"finding":"Gingerenone A directly binds IL-17RA protein (confirmed by pull-down and SPR) and inhibits IL-17RA/Act1-mediated downstream signaling; lentivirus-mediated IL-17RA/Act1 knockdown impaired GA's protective effects against DSS-induced intestinal inflammation.","method":"Pull-down assay, surface plasmon resonance, molecular dynamics simulation, lentiviral knockdown, in vivo colitis model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR plus pull-down binding confirmation plus functional KD validation in vivo, single lab","pmids":["38639442"],"is_preprint":false},{"year":2005,"finding":"IL-17R (IL-17RA) is expressed on human airway smooth muscle (ASM) cells; IL-17 induces CXCL-8 production from ASM cells via a transcriptional mechanism dependent on NF-κB and AP-1 binding sites in the CXCL-8 promoter.","method":"Immunostaining, surface receptor detection, transcriptional inhibitor (actinomycin D), promoter reporter assay with site-directed mutation, neutralizing antibody","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter mutagenesis plus pharmacological inhibition established transcriptional mechanism, single lab","pmids":["15893694"],"is_preprint":false},{"year":2016,"finding":"Complete autosomal recessive IL-17RA deficiency in 21 patients abolished cellular responses to IL-17A/F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes; alleles creating premature stop codons upstream of the transmembrane domain prevented surface receptor expression, while those downstream or the missense D387N allele permitted surface expression but all abolished signaling.","method":"Patient genetic analysis, surface receptor expression by flow cytometry, functional IL-17 response assays in fibroblasts and leukocytes","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — natural human loss-of-function variants with direct functional validation across 21 patients and 12 alleles, multiple orthogonal methods","pmids":["27930337"],"is_preprint":false},{"year":2019,"finding":"IL-17A-induced fibrogenic response in lung fibroblasts is mediated through NF-κB signaling and requires JAK2 (but not JAK1/JAK3) downstream of IL-17RA; siRNA silencing of IL-17RA attenuated ECM production, myofibroblast transdifferentiation, and cell proliferation in response to IL-17A.","method":"siRNA knockdown, selective JAK inhibitors (AZD1480 vs. tofacitinib), Western blotting, proliferation and ECM assays","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus pharmacological inhibitor with specific JAK2 selectivity established, single lab","pmids":["30604628"],"is_preprint":false},{"year":2019,"finding":"IL-17RA signaling in Trypanosoma cruzi-infected mice is intrinsically required in CD8+ T cells for survival and effector function; IL-17A in vitro downregulated pro-apoptotic BAD and promoted activated CD8+ T cell survival; IL-17RA-deficient T. cruzi-specific CD8+ T cells showed increased apoptosis and dysfunction.","method":"IL-17RA KO mouse, adoptive transfer of IL-17RA-/- vs. WT T cells, in vitro recombinant IL-17 treatment, transcriptomic profiling, PD-L1 blockade","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer establishing cell-intrinsic requirement plus in vitro mechanistic validation, single lab","pmids":["30364284"],"is_preprint":false},{"year":2025,"finding":"IL-17RA in intestinal epithelial cells (IECs) suppresses EMT by constraining EGFR expression and Src activation; IL-17RA in macrophages is required for Syk activation upon dectin-1 engagement with fungi, and for IL-18 release and CD8+ T cell anti-tumor immunity; these represent two distinct tumor-suppressive IL-17RA mechanisms in colorectal cancer.","method":"Cell-type-specific conditional KO (IEC and macrophage), tumor models, Syk activation assay, immune cell profiling","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual cell-type-specific conditional KO with mechanistic pathway identification for each, multiple orthogonal readouts","pmids":["40023157"],"is_preprint":false},{"year":2024,"finding":"TCF4 negatively regulates IL-17C; IL-17C stimulation of keratinocytes decreases TCF4 and increases NFKBIZ and ZC3H12A in an IL-17RA/IL-17RE-dependent manner, creating an autocrine inflammatory feedback loop; genetic elimination of Il17ra and Il17re reversed the loop in a murine dermatitis model.","method":"siRNA knockdown, conditional KO mouse (KC-Tie2), promoter analysis, gene expression profiling","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus KO mouse with rescue, mechanistic feedback loop established, single lab","pmids":["38470486"],"is_preprint":false},{"year":2018,"finding":"IL-17A/IL-17RA signaling promotes NSCLC cell migration and invasion via the p38 MAPK pathway; IL-17RA overexpression increased p38 phosphorylation and MMP-2/MMP-9 expression; p38 MAPK inhibitor SB203580 suppressed migration and invasion; MMP-2 and MMP-9 are downstream of IL-17RA/p38.","method":"IL-17RA overexpression, p38 MAPK inhibitor, wound healing/Transwell invasion assays, Western blotting","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pharmacological inhibitor plus OE with functional invasion readout, single lab","pmids":["30564960"],"is_preprint":false},{"year":2021,"finding":"Conditional deletion of IL-17RA in osteoclast precursors (LysM-Cre) increased trabecular bone mass and decreased osteoclast number in vivo; in vitro osteoclast formation was reduced, associated with lower abundance of osteoclast precursors.","method":"Conditional KO mouse (LysM-Cre), micro-CT, histomorphometry, in vitro osteoclastogenesis assay","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO with in vivo bone phenotype and in vitro validation, single lab","pmids":["34973492"],"is_preprint":false},{"year":2018,"finding":"IL-17RA expression in mesenchymal stem cells (MSCs) is required for their immunosuppressive function; IL-17RA-/- MSCs showed reduced VCAM1, ICAM1, and PD-L1 expression, could not suppress Th17 proliferation, and failed to reduce EAE severity or generate regulatory T cells in vivo.","method":"IL-17RA KO MSC transplantation, EAE model, flow cytometry, in vitro suppression assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell adoptive transfer with in vivo disease model and mechanistic effector molecule identification, single lab","pmids":["29760692"],"is_preprint":false},{"year":2018,"finding":"IL-17RA signaling in hepatocytes regulates IL-6 production by non-parenchymal cell recruitment, which in turn triggers hepatocyte proliferation; IL-17RA-/- mice showed delayed early-gene expression and delayed G1/S phase transition after partial hepatectomy.","method":"IL-17RA KO mouse, partial hepatectomy model, gene expression analysis, cell cycle analysis","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO mouse with functional proliferation readout and IL-6 as mediator, mechanism partly inferred, single lab","pmids":["30395772"],"is_preprint":false},{"year":2011,"finding":"IL-17RA PLAD (pre-ligand assembly domain) mediates receptor-chain associations essential for signaling; lentiviral IL-17RA PLAD-Ig expression in spontaneously hypertensive rats reduced collagen deposition, MMP-2/9 expression, and TIMP-1/2 levels, improving diastolic cardiac function.","method":"Lentiviral PLAD-Ig overexpression in vivo, echocardiography, immunoblotting for ECM proteins","journal":"Experimental and molecular pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single in vivo pharmacological intervention without direct PLAD-receptor interaction measurement, single lab","pmids":["21530504"],"is_preprint":false},{"year":2019,"finding":"IL-17B uses IL-17RA and IL-17RB receptor subunits to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT, and CD4+CRTH2+ Th2 cells; this activity was dependent on both IL-17RA and IL-17RB.","method":"Receptor blocking antibodies, primary human lymphocyte functional assays, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with primary human cells, established novel ligand-receptor pairing, single lab","pmids":["30770417"],"is_preprint":false},{"year":2019,"finding":"IL-17C signals through the IL-17RA/IL-17RE receptor heterodimer in oral epithelial cells to stimulate production of TNF-α; IL-17C mRNA was expressed in cultured human oral keratinocytes that also expressed IL-17RA and IL-17RE; neutralizing IL-17C or IL-17R antibodies attenuated these responses.","method":"qRT-PCR, IL-17C stimulation assay, neutralizing antibody blockade, immunohistochemistry","journal":"Journal of oral pathology & medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — neutralizing antibody approach in primary cells, single lab, limited mechanistic depth","pmids":["23834281"],"is_preprint":false},{"year":2012,"finding":"The IL-17A/IL-17RA axis promotes aortic arch inflammation during atherosclerosis by inducing TNFα and CXCL2 and accelerating neutrophil/monocyte recruitment; IL-17RA supports monocyte adherence to explanted aortas; adoptively transferred monocytes and neutrophils showed impaired homing to IL-17RA-deficient aortas.","method":"Il17ra-/- Apoe-/- mouse model, flow cytometry, ex vivo adhesion assay, short-term homing experiments with adoptive transfer","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus ex vivo adhesion plus adoptive transfer, multiple orthogonal methods","pmids":["22302786"],"is_preprint":false},{"year":2012,"finding":"IL-17RA signaling is required for CXCL1/CXCL2-dependent neutrophil recruitment during T. cruzi infection; recruited neutrophils secrete IL-10 and suppress T cell proliferation and IFN-γ production in an IL-10-dependent manner; adoptive transfer of WT neutrophils restored this suppressive phenotype and improved survival in IL-17RA KO mice.","method":"IL-17RA KO mouse, neutrophil depletion (anti-Ly6G), adoptive transfer, in vitro suppression assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO plus depletion plus adoptive transfer rescue establishing IL-17RA→CXCL1/2→neutrophil→IL-10 suppression axis","pmids":["22577359"],"is_preprint":false}],"current_model":"IL-17RA is a shared receptor subunit that forms heteromeric complexes (with IL-17RC, IL-17RB, or IL-17RE) to transduce signals from multiple IL-17 family ligands (IL-17A, IL-17F, IL-17A/F, IL-17B, IL-17C, IL-17E/IL-25); upon cytokine binding, IL-17RA dimerizes to form a 2:2:2 hexameric signalosome, and its extended SEFIR/TILL intracellular domain recruits Act1 via CC'-loop interactions to activate TRAF6 ubiquitination, NF-κB, and MAPK (ERK, p38, JNK) pathways, driving expression of chemokines (CXCL1/2/5/8, CCL20), inflammatory cytokines (IL-6), and matrix metalloproteases; additional context-specific signaling includes JAK2/STAT3 in fibroblasts, Rab35/PKCα in airway smooth muscle, Syk in macrophages, and ATOH1 induction in intestinal stem cells; natural loss-of-function mutations in humans abolish responses to IL-17A/F and IL-25, causing chronic mucocutaneous candidiasis and staphylococcal infections, establishing its non-redundant role in mucocutaneous immunity."},"narrative":{"mechanistic_narrative":"IL17RA is a shared receptor subunit that nucleates signaling for multiple IL-17 family cytokines by pairing with distinct co-receptors—IL-17RC for IL-17A, IL-17F, and the IL-17A/F heterodimer [PMID:18684971, PMID:21109515], IL-17RB for IL-25/IL-17E and IL-17B [PMID:18768888, PMID:30770417], and IL-17RE for IL-17C [PMID:38470486, PMID:23834281]. Cytokine binding drives IL-17RA dimerization and assembly of a 2:2:2 hexameric IL-17RA/IL-17RC/IL-17A signalosome, and dimerization-defective IL-17RA mutants lose downstream gene induction [PMID:36260993]; structural studies of IL-17RC bound to IL-17F reveal a competing 2:1 cytokine-binding geometry [PMID:32187518]. Signal transduction requires an extended SEFIR+TILL intracellular module whose CC' loop directly binds the adaptor Act1, an interaction necessary for TRAF6 ubiquitination and downstream output [PMID:20729198, PMID:22045852], with RKIP acting as a positive scaffold that stabilizes the IL-17RA–Act1 complex [PMID:29674348]. Engagement activates NF-κB, AP-1, and the ERK/p38/JNK MAPK cascades to drive chemokine and cytokine programs (IL-6, IL-8, CCL20, ELR+ CXC chemokines, MMPs) [PMID:21109515, PMID:17644350, PMID:18097068], with context-specific use of STAT3/JAK2 in fibroblasts [PMID:28898718, PMID:30604628], Rab35/PKCα-fascin in airway smooth muscle [PMID:30683702], and Syk in macrophages [PMID:40023157]. Through these pathways IL17RA governs barrier and tissue physiology, including neutrophil recruitment to lung [PMID:19783685, PMID:26871571], intestinal secretory-lineage commitment via ATOH1 [PMID:35081371], control of microbiota and gut-liver immunity [PMID:31747600], and tumor-suppressive epithelial and macrophage functions in colorectal cancer [PMID:40023157]. Complete autosomal recessive IL17RA deficiency in humans abolishes responses to IL-17A/F and IL-25 and causes chronic mucocutaneous candidiasis and staphylococcal infection, establishing its non-redundant role in mucocutaneous immunity [PMID:27930337].","teleology":[{"year":2008,"claim":"Established that IL17RA is not a solitary receptor but functions in obligate heteromeric complexes with co-receptors to read distinct IL-17 family ligands.","evidence":"siRNA knockdown plus SPR binding for IL-17A/F via IL-17RA/IL-17RC, and KO mice plus blocking antibody for IL-25 via IL-17RA/IL-17RB","pmids":["18684971","18768888"],"confidence":"High","gaps":["Stoichiometry of the assembled complexes not resolved","Mechanism coupling ligand binding to intracellular signaling not addressed"]},{"year":2011,"claim":"Defined the molecular basis of intracellular signal initiation by mapping the Act1-binding determinant to the CC' loop of an extended SEFIR+TILL domain, distinguishing receptor engagement from downstream output.","evidence":"Structure-function deletion mutagenesis, SPR with CC' loop peptide, and a cell-permeable decoy peptide blocking signaling in vitro and in vivo","pmids":["20729198","22045852"],"confidence":"High","gaps":["Atomic structure of the SEFIR-SEFIR interface not determined","How TRAF6 ubiquitination is mechanistically licensed downstream of Act1 not fully resolved"]},{"year":2007,"claim":"Showed that the IL17RA/IL-17RC pair converges on NF-κB, AP-1, and ERK/p38/JNK MAPK to drive chemokine and inflammatory cytokine programs across epithelial and stromal cell types.","evidence":"siRNA knockdown of either receptor with MAPK Western blotting, transcription factor activation assays, ELISA, and microarray in synoviocytes, gastric cells, and airway smooth muscle","pmids":["17644350","21109515","18097068","15893694"],"confidence":"Medium","gaps":["Relative contributions of each MAPK branch to specific gene targets not dissected","Cell-type determinants of pathway selection unclear"]},{"year":2020,"claim":"Resolved the architecture of the signaling-competent receptor, revealing ligand-induced IL17RA dimerization into a 2:2:2 hexamer and an alternative IL-17RC-centered 2:1 geometry, linking assembly to function.","evidence":"X-ray crystallography of IL-17RA/IL-17RC ectodomains with IL-17A/IL-17F, biophysical binding, and dimerization-defective mutants tested in keratinocytes","pmids":["32187518","36260993"],"confidence":"High","gaps":["Whether IL-17RA-independent IL-17RC signaling occurs in cells not directly demonstrated","Conformational coupling from ectodomain assembly to intracellular SEFIR not visualized"]},{"year":2018,"claim":"Identified positive and small-molecule modulators of the IL17RA–Act1 axis, expanding the regulatory and pharmacological control points of the receptor.","evidence":"Co-IP and KO/EAE for RKIP as a scaffold; structure-based and SPR/pull-down identification of cyanidin, HAP peptide, and gingerenone A blocking the IL-17A/IL17RA interface","pmids":["29674348","28223414","27184415","38639442"],"confidence":"Medium","gaps":["Endogenous regulation of RKIP-IL17RA coupling in human disease not established","Inhibitor specificity versus other IL-17 family receptors not fully delineated"]},{"year":2022,"claim":"Revealed cell-type-specific, non-canonical IL17RA signaling outputs beyond NF-κB/MAPK, including cytoskeletal, metabolic, and differentiation programs.","evidence":"Conditional KO and co-IP for Rab35/PKCα-fascin in airway smooth muscle, STAT3/JAK2 axes in fibroblasts, STAT3/FABP4 in ovarian cancer, and ATOH1 induction in intestinal stem cells/organoids","pmids":["30683702","30604628","31802182","35081371"],"confidence":"High","gaps":["How a single receptor selects among these divergent outputs is unresolved","Direct biochemical links from IL17RA to JAK2/STAT3 not fully mapped"]},{"year":2019,"claim":"Demonstrated tissue-protective and barrier functions of IL17RA in epithelial and stromal compartments, including microbiota control, gut-liver immunity, and tumor suppression.","evidence":"Tissue-specific conditional KO with 16S sequencing, hepatitis and colorectal tumor models, Syk activation assays, and bacterial/viral challenge models","pmids":["31747600","29760692","40023157","19783685","26871571","34516780"],"confidence":"High","gaps":["Compartment-specific signaling mechanisms not uniformly defined","Translation of protective epithelial roles to human disease incompletely characterized"]},{"year":2016,"claim":"Established the non-redundant human in vivo function of IL17RA by showing that biallelic loss-of-function abolishes responses to IL-17A/F and IL-25 and causes mucocutaneous infection susceptibility.","evidence":"Genetic analysis of 21 patients with surface expression flow cytometry and functional IL-17 response assays in fibroblasts and leukocytes","pmids":["27930337"],"confidence":"High","gaps":["Genotype-phenotype variation across alleles not fully explained","Contribution of individual ligand pathways to specific clinical features not separated"]},{"year":2022,"claim":"Identified post-transcriptional and isoform-level regulation of IL17RA abundance as a control point in chronic inflammation.","evidence":"MeRIP-seq with FTO knockdown/overexpression in liver injury models, and RT-PCR/Western detection of a soluble splice isoform lacking the transmembrane domain","pmids":["36172147","24084331"],"confidence":"Medium","gaps":["Functional role of the soluble isoform (decoy vs. agonist) not tested","Physiological triggers of FTO-mediated IL17RA regulation unknown"]},{"year":null,"claim":"How a single shared receptor subunit selects among NF-κB/MAPK, STAT3, cytoskeletal, and differentiation outputs in a cell-type- and ligand-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking co-receptor identity to downstream pathway choice","Structural basis of intracellular signalosome assembly in cells not determined","Function of the soluble IL17RA isoform unestablished"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,9,26]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,36,37]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,25,26]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,14,26,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,29]}],"complexes":["IL-17RA/IL-17RC receptor complex","IL-17RA/IL-17RB receptor complex","IL-17RA/IL-17RE receptor complex","IL-17R-Act1 signaling complex"],"partners":["IL17RC","IL17RB","IL17RE","TRAF3IP2","TRAF6","PEBP1","RAB35","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96F46","full_name":"Interleukin-17 receptor A","aliases":["CDw217"],"length_aa":866,"mass_kda":96.1,"function":"Receptor for IL17A and IL17F, major effector cytokines of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity. Receptor for IL17A (PubMed:17911633, PubMed:9367539). Receptor for IL17F (PubMed:17911633, PubMed:19838198). Binds to IL17A with higher affinity than to IL17F (PubMed:17911633). Binds IL17A and IL17F homodimers as part of a heterodimeric complex with IL17RC (PubMed:16785495). Also binds heterodimers formed by IL17A and IL17F as part of a heterodimeric complex with IL17RC (PubMed:18684971). Cytokine binding triggers homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter, leading to TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways, ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:16785495, PubMed:17911633, PubMed:18684971, PubMed:21350122, PubMed:24120361). Involved in antimicrobial host defense primarily promoting neutrophil activation and recruitment at infection sites to destroy extracellular bacteria and fungi (By similarity). In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells (By similarity). Plays a role in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection. Stimulates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity). Involved in antiviral host defense through various mechanisms. Enhances immunity against West Nile virus by promoting T cell cytotoxicity. Contributes to Influenza virus clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense (By similarity). Receptor for IL17C as part of a heterodimeric complex with IL17RE (PubMed:21993848) (Microbial infection) Receptor for SARS coronavirus-2/SARS-CoV-2 virus protein ORF8, leading to IL17 pathway activation and an increased secretion of pro-inflammatory factors through activating NF-kappa-B signaling pathway","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q96F46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IL17RA","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"613956","title":"CANDIDIASIS, FAMILIAL, 6; CANDF6","url":"https://www.omim.org/entry/613956"},{"mim_id":"613953","title":"IMMUNODEFICIENCY 51; IMD51","url":"https://www.omim.org/entry/613953"},{"mim_id":"610925","title":"INTERLEUKIN 17 RECEPTOR C; IL17RC","url":"https://www.omim.org/entry/610925"},{"mim_id":"607043","title":"TRAF3-INTERACTING PROTEIN 2; TRAF3IP2","url":"https://www.omim.org/entry/607043"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":33.1}],"url":"https://www.proteinatlas.org/search/IL17RA"},"hgnc":{"alias_symbol":["hIL-17R","IL-17RA","CDw217","CD217"],"prev_symbol":["IL17R"]},"alphafold":{"accession":"Q96F46","domains":[{"cath_id":"2.60.40.2160","chopping":"34-194","consensus_level":"high","plddt":90.0517,"start":34,"end":194},{"cath_id":"2.60.40.2150","chopping":"204-302","consensus_level":"high","plddt":90.699,"start":204,"end":302},{"cath_id":"3.40.50.11530","chopping":"379-589","consensus_level":"high","plddt":86.7589,"start":379,"end":589}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96F46-F1-predicted_aligned_error_v6.png","plddt_mean":68.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RA","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RA"},"sequence":{"accession":"Q96F46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96F46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96F46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96F46"}},"corpus_meta":[{"pmid":"24918373","id":"PMC_24918373","title":"Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis.","date":"2014","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24918373","citation_count":308,"is_preprint":false},{"pmid":"19783685","id":"PMC_19783685","title":"Critical role of IL-17RA in immunopathology of influenza infection.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19783685","citation_count":298,"is_preprint":false},{"pmid":"18768888","id":"PMC_18768888","title":"Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18768888","citation_count":279,"is_preprint":false},{"pmid":"18684971","id":"PMC_18684971","title":"The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18684971","citation_count":246,"is_preprint":false},{"pmid":"33789737","id":"PMC_33789737","title":"Exosomes derived from human adipose mesenchymal stem cells attenuate hypertrophic scar fibrosis by miR-192-5p/IL-17RA/Smad axis.","date":"2021","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33789737","citation_count":217,"is_preprint":false},{"pmid":"21647421","id":"PMC_21647421","title":"IL-17RA is required for CCL2 expression, macrophage recruitment, and emphysema in response to cigarette smoke.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21647421","citation_count":186,"is_preprint":false},{"pmid":"30604628","id":"PMC_30604628","title":"Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease.","date":"2019","source":"American journal of physiology. 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surface plasmon resonance showed IL-17A and IL-17F bind IL-17RC with comparable affinities but bind IL-17RA with different affinities; siRNA knockdown of IL-17RA or IL-17RC abolished heterodimer activity in bronchial epithelial cells.\",\n      \"method\": \"siRNA knockdown, surface plasmon resonance (SPR), functional cytokine assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPR biophysical binding measurements combined with siRNA knockdown in primary cells, single lab but two orthogonal methods\",\n      \"pmids\": [\"18684971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-25 (IL-17E)-mediated activities require both IL-17RB and IL-17RA; splenocytes from IL-17RA KO mice failed to produce IL-5 or IL-13 in response to IL-25, and IL-17RA KO mice failed to respond to intranasal IL-25; blocking anti-IL-17RA mAb prevented IL-25 activity in human cells.\",\n      \"method\": \"Knockout mouse model, antagonistic antibody blockade, in vitro cytokine assay, in vivo pulmonary inflammation model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody blockade replicated both in vivo and in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"18768888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-17RA signaling requires an extended SEFIR domain (termed SEFIR+TILL) beyond the previously defined SEFIR motif for downstream signaling; Act1 recruitment alone is not sufficient for signaling, but TRAF6 ubiquitination correlates tightly with functional receptors; deletion of the CC' loop (not the BB' loop) from IL-17RA abolished Act1-IL-17RA interaction.\",\n      \"method\": \"Structure-function mutagenesis, receptor deletion constructs, functional reporter assays, ubiquitination assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with multiple deletion constructs and functional readouts in a single rigorous study\",\n      \"pmids\": [\"20729198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The CC' loop of the SEFIR domain of IL-17RA is required for Act1 binding; SPR showed a CC' loop-based peptide directly binds IL-17RA; a cell-permeable CC' loop decoy peptide inhibited IL-17- and IL-25-mediated signaling in vitro and pulmonary inflammation in vivo.\",\n      \"method\": \"Surface plasmon resonance, deletion mutagenesis, cell-permeable decoy peptide in vitro and in vivo\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR binding assay plus mutagenesis plus in vivo functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22045852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A- and IL-17F-induced NF-κB and MAPK (ERK, p38, JNK) activation and IL-6/IL-8/CCL20 secretion in human rheumatoid synoviocytes; siRNA silencing of either receptor nearly abolished IL-6 expression mediated by IL-17A.\",\n      \"method\": \"siRNA knockdown, MAPK western blotting, ELISA, microarray\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple downstream readouts, consistent with earlier findings in same cell type\",\n      \"pmids\": [\"21109515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A-mediated activation of ERK, p38, JNK, AP-1, and p65 NF-κB in gastric adenocarcinoma cells; siRNA knockdown of either receptor nearly abolished IL-17A-induced c-Jun and p65 activation.\",\n      \"method\": \"siRNA knockdown, MAPK western blotting, transcription factor binding assay (TransAM), ELISA\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA with multiple downstream signaling readouts, single lab\",\n      \"pmids\": [\"17644350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Both IL-17RA and IL-17RC are required for IL-17A-induced ELR+ CXC chemokine (CXCL1, CXCL5, CXCL6) expression in synoviocytes; siRNA silencing of either receptor reduced IL-17A-induced IL-6, IL-8, and CCL-20 secretion.\",\n      \"method\": \"siRNA knockdown, ELISA, microarray\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA plus microarray in primary human synoviocytes, single lab\",\n      \"pmids\": [\"18097068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RKIP directly interacts with IL-17RA and Act1 to promote formation of the IL-17R-Act1 complex, resulting in enhanced MAPK and NF-κB activation and downstream cytokine production; RKIP deficiency in mice ameliorated EAE symptoms and reduced IL-17R-mediated proinflammatory responses.\",\n      \"method\": \"Co-immunoprecipitation, adoptive T cell transfer, KO mouse model, NF-κB/MAPK reporter assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying novel binding partner plus in vivo KO rescue, single lab\",\n      \"pmids\": [\"29674348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F revealed that IL-17RC forms a symmetrical 2:1 complex with IL-17F, competing with IL-17RA for cytokine binding; biophysical studies showed IL-17A and IL-17A/F heterodimer also form 2:1 complexes with IL-17RC, suggesting IL-17RA-independent signaling is possible.\",\n      \"method\": \"X-ray crystallography, biophysical binding assays (SPR/ITC)\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biophysical validation, reveals unexpected stoichiometry of the IL-17RC:IL-17F complex\",\n      \"pmids\": [\"32187518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17A, IL-17F, and IL-17A/F induce IL-17RA dimerization; crystal structure of the extracellular domains of IL-17RA and IL-17RC in complex with IL-17A revealed a 2:2:2 hexameric signaling assembly; dimerization-defective IL-17RA mutants showed reduced IL-36γ and CXCL1 mRNA induction in human keratinocytes.\",\n      \"method\": \"X-ray crystallography, biophysical assays, mutagenesis, functional mRNA expression assay in keratinocytes\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional validation, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"36260993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cyanidin specifically binds to an IL-17A binding site within IL-17RA (structure-based identification) and inhibits the IL-17A/IL-17RA interaction; this blocked IL-17A-induced skin hyperplasia and attenuated TH17-driven airway hyperreactivity in mice.\",\n      \"method\": \"Structure-based virtual screening, binding assays, in vivo murine models of psoriasis and asthma\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural modeling plus in vivo functional validation, mechanism confirmed by pharmacological inhibition\",\n      \"pmids\": [\"28223414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A 15-residue phage-display-derived peptide (HAP) binds IL-17A and blocks IL-17A/IL-17RA interaction; crystal structure revealed two HAP molecules bind one IL-17A dimer symmetrically with the C-terminal helix directly blocking the IL-17RA binding region of IL-17A.\",\n      \"method\": \"Phage display, saturation mutagenesis, X-ray crystallography, primary human cell functional assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation in primary cells, multiple orthogonal methods\",\n      \"pmids\": [\"27184415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A/IL-17RA signaling promotes fatty acid uptake in ovarian cancer cells via the IL-17RA/p-STAT3/FABP4 axis; IL-17RA was required for IL-17A-induced STAT3 phosphorylation and FABP4 upregulation, promoting cellular palmitic acid uptake.\",\n      \"method\": \"In vitro cytokine stimulation, Western blotting, IL-17A-deficient mouse orthotopic model, siRNA knockdown\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IL-17A-deficient mouse model plus in vitro mechanistic pathway delineation, single lab\",\n      \"pmids\": [\"31802182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17RA is required for CCL2 expression and MMP12 induction in response to cigarette smoke; IL-17RA-/- mice failed to develop emphysema after 6 months of cigarette smoke exposure, establishing IL-17RA signaling as necessary for smoke-induced COPD pathology.\",\n      \"method\": \"IL-17RA knockout mouse model, qPCR for CCL2 and MMP12, histological assessment of emphysema\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with specific molecular and histological readouts over 6-month exposure period\",\n      \"pmids\": [\"21647421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RA signaling is required for neutrophil migration and myeloperoxidase increases in the lung after influenza infection; IL-17RA-/- mice showed reduced oxidized phospholipids and were protected from acute lung injury, but IL-17RA was dispensable for CD8+ T cell recruitment and viral clearance.\",\n      \"method\": \"IL-17RA knockout mouse model, flow cytometry, MPO assay, viral clearance assay, lipid oxidation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple orthogonal readouts distinguishing required vs. dispensable functions\",\n      \"pmids\": [\"19783685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-17RA is required for optimal localization of follicular Th (TFH) cells in the germinal center light zone; IL-17 signaling upregulates RGS16 in TFH cells to promote TFH-B cell conjugate formation; IL-17RA deficiency in BXD2 mice abrogated autoantibody-forming B cell generation without affecting total TFH numbers.\",\n      \"method\": \"IL-17RA knockout mouse (BXD2-Il17ra-/-), adenoviral IL-17R:Fc blockade, immunofluorescence, in vitro conjugate formation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus acute blockade, mechanistic link to RGS16 identified, single lab\",\n      \"pmids\": [\"23858031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17RA signaling in Lgr5+ intestinal stem cells induces ATOH1 transcription factor expression to promote secretory epithelial cell lineage commitment (Paneth, tuft, goblet, enteroendocrine cells); conditional deletion models showed IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury; IL-17A stimulation of human intestinal organoids rescued secretory cell differentiation.\",\n      \"method\": \"Conditional knockout mouse models, human intestinal organoids, lineage tracing, immunofluorescence\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional deletion models plus human organoid validation, replicated across cell types and species\",\n      \"pmids\": [\"35081371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A promotes airway smooth muscle contraction by recruiting Rab35 (via DennD1C GEF) to the IL-17R/Act1 complex, activating PKCα and phosphorylating fascin at Ser39, enabling F-actin/myosin stress fiber formation; cell-type-specific deletion of IL-17R or Act1 in airway smooth muscle cells confirmed direct role.\",\n      \"method\": \"Cell-type-specific conditional KO, co-immunoprecipitation, Rab35 knockdown, PKCα inhibitor, contraction assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — conditional KO plus co-IP plus specific pharmacological inhibition with direct contractility readout\",\n      \"pmids\": [\"30683702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO (a m6A demethylase) suppresses m6A mRNA methylation of IL-17RA, leading to increased IL-17RA expression; knockdown and overexpression of FTO in vitro and in vivo demonstrated FTO as the primary m6A modulator of IL-17RA, and increased IL-17RA promoted chronic hepatic inflammation.\",\n      \"method\": \"MeRIP-seq, FTO knockdown/overexpression, murine NAFLD/liver injury models, Western blotting\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus functional KD/OE with in vivo validation, single lab\",\n      \"pmids\": [\"36172147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A soluble isoform of human IL-17RA is generated by alternative splicing that removes exon 11 encoding the transmembrane domain; RT-PCR confirmed this variant in multiple human tissues and the secreted protein was detected in culture media by Western blotting.\",\n      \"method\": \"RT-PCR, Western blotting of conditioned media\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal detection methods (RT-PCR and Western blot) for a novel isoform, single lab\",\n      \"pmids\": [\"24084331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA signaling in intestinal epithelial cells regulates microbial composition and constrains translocation of TLR9 ligands (CpG DNA); intestinal epithelium-specific IL-17RA deletion caused microbiome dysbiosis, increased CpG DNA translocation driving hepatic IL-18 production, and exacerbated immune-driven hepatitis.\",\n      \"method\": \"Intestinal epithelium-specific IL-17RA conditional KO mouse, 16S microbiome sequencing, hepatitis model, cytokine measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with mechanistic chain from microbiome dysbiosis to IL-18 to hepatitis, multiple readouts\",\n      \"pmids\": [\"31747600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17 signaling in fibroblasts requires IL-17RA/STAT3 axis to induce SHP-2, Cyr61, IL-23, GM-CSF and RANKL expression in rheumatoid arthritis fibroblast-like synoviocytes; siRNA knockdown of IL-17RA reversed IL-17-induced RANKL expression and osteoclastogenic potential.\",\n      \"method\": \"siRNA knockdown, STAT3 inhibitor, co-culture osteoclastogenesis assay, Western blotting\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA plus pathway inhibitor plus functional osteoclastogenesis assay, single lab\",\n      \"pmids\": [\"28898718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RA/Act1 signaling is required for IL-17R-induced lung immunity against Klebsiella; conditional deletion showed IL-17R signaling specifically in fibroblasts is required for lung-specific protective immunity (not systemic antibody-mediated protection) in a mucosal vaccine model.\",\n      \"method\": \"Cell-type-specific conditional IL-17R KO mouse, adoptive transfer, mucosal vaccine model, bacterial challenge\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO isolating fibroblast-specific function of IL-17R, single lab\",\n      \"pmids\": [\"34516780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA signaling in non-hematopoietic cells controls CXCL-1 and CXCL-5 production to recruit neutrophils to the lung during the adaptive immune response to mycobacteria; CXCL-1 and CXCL-5 instillation reconstituted neutrophil recruitment in IL-17RA-/- mice.\",\n      \"method\": \"IL-17RA KO mouse, bone marrow transplantation, cytokine instillation rescue experiment, flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO plus rescue experiment identifying IL-17RA in non-hematopoietic cells as key source, single lab\",\n      \"pmids\": [\"26871571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Gingerenone A directly binds IL-17RA protein (confirmed by pull-down and SPR) and inhibits IL-17RA/Act1-mediated downstream signaling; lentivirus-mediated IL-17RA/Act1 knockdown impaired GA's protective effects against DSS-induced intestinal inflammation.\",\n      \"method\": \"Pull-down assay, surface plasmon resonance, molecular dynamics simulation, lentiviral knockdown, in vivo colitis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR plus pull-down binding confirmation plus functional KD validation in vivo, single lab\",\n      \"pmids\": [\"38639442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-17R (IL-17RA) is expressed on human airway smooth muscle (ASM) cells; IL-17 induces CXCL-8 production from ASM cells via a transcriptional mechanism dependent on NF-κB and AP-1 binding sites in the CXCL-8 promoter.\",\n      \"method\": \"Immunostaining, surface receptor detection, transcriptional inhibitor (actinomycin D), promoter reporter assay with site-directed mutation, neutralizing antibody\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter mutagenesis plus pharmacological inhibition established transcriptional mechanism, single lab\",\n      \"pmids\": [\"15893694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Complete autosomal recessive IL-17RA deficiency in 21 patients abolished cellular responses to IL-17A/F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes; alleles creating premature stop codons upstream of the transmembrane domain prevented surface receptor expression, while those downstream or the missense D387N allele permitted surface expression but all abolished signaling.\",\n      \"method\": \"Patient genetic analysis, surface receptor expression by flow cytometry, functional IL-17 response assays in fibroblasts and leukocytes\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — natural human loss-of-function variants with direct functional validation across 21 patients and 12 alleles, multiple orthogonal methods\",\n      \"pmids\": [\"27930337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17A-induced fibrogenic response in lung fibroblasts is mediated through NF-κB signaling and requires JAK2 (but not JAK1/JAK3) downstream of IL-17RA; siRNA silencing of IL-17RA attenuated ECM production, myofibroblast transdifferentiation, and cell proliferation in response to IL-17A.\",\n      \"method\": \"siRNA knockdown, selective JAK inhibitors (AZD1480 vs. tofacitinib), Western blotting, proliferation and ECM assays\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus pharmacological inhibitor with specific JAK2 selectivity established, single lab\",\n      \"pmids\": [\"30604628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RA signaling in Trypanosoma cruzi-infected mice is intrinsically required in CD8+ T cells for survival and effector function; IL-17A in vitro downregulated pro-apoptotic BAD and promoted activated CD8+ T cell survival; IL-17RA-deficient T. cruzi-specific CD8+ T cells showed increased apoptosis and dysfunction.\",\n      \"method\": \"IL-17RA KO mouse, adoptive transfer of IL-17RA-/- vs. WT T cells, in vitro recombinant IL-17 treatment, transcriptomic profiling, PD-L1 blockade\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer establishing cell-intrinsic requirement plus in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"30364284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RA in intestinal epithelial cells (IECs) suppresses EMT by constraining EGFR expression and Src activation; IL-17RA in macrophages is required for Syk activation upon dectin-1 engagement with fungi, and for IL-18 release and CD8+ T cell anti-tumor immunity; these represent two distinct tumor-suppressive IL-17RA mechanisms in colorectal cancer.\",\n      \"method\": \"Cell-type-specific conditional KO (IEC and macrophage), tumor models, Syk activation assay, immune cell profiling\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual cell-type-specific conditional KO with mechanistic pathway identification for each, multiple orthogonal readouts\",\n      \"pmids\": [\"40023157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TCF4 negatively regulates IL-17C; IL-17C stimulation of keratinocytes decreases TCF4 and increases NFKBIZ and ZC3H12A in an IL-17RA/IL-17RE-dependent manner, creating an autocrine inflammatory feedback loop; genetic elimination of Il17ra and Il17re reversed the loop in a murine dermatitis model.\",\n      \"method\": \"siRNA knockdown, conditional KO mouse (KC-Tie2), promoter analysis, gene expression profiling\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus KO mouse with rescue, mechanistic feedback loop established, single lab\",\n      \"pmids\": [\"38470486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17A/IL-17RA signaling promotes NSCLC cell migration and invasion via the p38 MAPK pathway; IL-17RA overexpression increased p38 phosphorylation and MMP-2/MMP-9 expression; p38 MAPK inhibitor SB203580 suppressed migration and invasion; MMP-2 and MMP-9 are downstream of IL-17RA/p38.\",\n      \"method\": \"IL-17RA overexpression, p38 MAPK inhibitor, wound healing/Transwell invasion assays, Western blotting\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pharmacological inhibitor plus OE with functional invasion readout, single lab\",\n      \"pmids\": [\"30564960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Conditional deletion of IL-17RA in osteoclast precursors (LysM-Cre) increased trabecular bone mass and decreased osteoclast number in vivo; in vitro osteoclast formation was reduced, associated with lower abundance of osteoclast precursors.\",\n      \"method\": \"Conditional KO mouse (LysM-Cre), micro-CT, histomorphometry, in vitro osteoclastogenesis assay\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO with in vivo bone phenotype and in vitro validation, single lab\",\n      \"pmids\": [\"34973492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RA expression in mesenchymal stem cells (MSCs) is required for their immunosuppressive function; IL-17RA-/- MSCs showed reduced VCAM1, ICAM1, and PD-L1 expression, could not suppress Th17 proliferation, and failed to reduce EAE severity or generate regulatory T cells in vivo.\",\n      \"method\": \"IL-17RA KO MSC transplantation, EAE model, flow cytometry, in vitro suppression assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell adoptive transfer with in vivo disease model and mechanistic effector molecule identification, single lab\",\n      \"pmids\": [\"29760692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RA signaling in hepatocytes regulates IL-6 production by non-parenchymal cell recruitment, which in turn triggers hepatocyte proliferation; IL-17RA-/- mice showed delayed early-gene expression and delayed G1/S phase transition after partial hepatectomy.\",\n      \"method\": \"IL-17RA KO mouse, partial hepatectomy model, gene expression analysis, cell cycle analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO mouse with functional proliferation readout and IL-6 as mediator, mechanism partly inferred, single lab\",\n      \"pmids\": [\"30395772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17RA PLAD (pre-ligand assembly domain) mediates receptor-chain associations essential for signaling; lentiviral IL-17RA PLAD-Ig expression in spontaneously hypertensive rats reduced collagen deposition, MMP-2/9 expression, and TIMP-1/2 levels, improving diastolic cardiac function.\",\n      \"method\": \"Lentiviral PLAD-Ig overexpression in vivo, echocardiography, immunoblotting for ECM proteins\",\n      \"journal\": \"Experimental and molecular pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single in vivo pharmacological intervention without direct PLAD-receptor interaction measurement, single lab\",\n      \"pmids\": [\"21530504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17B uses IL-17RA and IL-17RB receptor subunits to induce type 2 cytokine secretion from human innate type 2 lymphocytes, NKT, and CD4+CRTH2+ Th2 cells; this activity was dependent on both IL-17RA and IL-17RB.\",\n      \"method\": \"Receptor blocking antibodies, primary human lymphocyte functional assays, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with primary human cells, established novel ligand-receptor pairing, single lab\",\n      \"pmids\": [\"30770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17C signals through the IL-17RA/IL-17RE receptor heterodimer in oral epithelial cells to stimulate production of TNF-α; IL-17C mRNA was expressed in cultured human oral keratinocytes that also expressed IL-17RA and IL-17RE; neutralizing IL-17C or IL-17R antibodies attenuated these responses.\",\n      \"method\": \"qRT-PCR, IL-17C stimulation assay, neutralizing antibody blockade, immunohistochemistry\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — neutralizing antibody approach in primary cells, single lab, limited mechanistic depth\",\n      \"pmids\": [\"23834281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The IL-17A/IL-17RA axis promotes aortic arch inflammation during atherosclerosis by inducing TNFα and CXCL2 and accelerating neutrophil/monocyte recruitment; IL-17RA supports monocyte adherence to explanted aortas; adoptively transferred monocytes and neutrophils showed impaired homing to IL-17RA-deficient aortas.\",\n      \"method\": \"Il17ra-/- Apoe-/- mouse model, flow cytometry, ex vivo adhesion assay, short-term homing experiments with adoptive transfer\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus ex vivo adhesion plus adoptive transfer, multiple orthogonal methods\",\n      \"pmids\": [\"22302786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-17RA signaling is required for CXCL1/CXCL2-dependent neutrophil recruitment during T. cruzi infection; recruited neutrophils secrete IL-10 and suppress T cell proliferation and IFN-γ production in an IL-10-dependent manner; adoptive transfer of WT neutrophils restored this suppressive phenotype and improved survival in IL-17RA KO mice.\",\n      \"method\": \"IL-17RA KO mouse, neutrophil depletion (anti-Ly6G), adoptive transfer, in vitro suppression assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO plus depletion plus adoptive transfer rescue establishing IL-17RA→CXCL1/2→neutrophil→IL-10 suppression axis\",\n      \"pmids\": [\"22577359\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RA is a shared receptor subunit that forms heteromeric complexes (with IL-17RC, IL-17RB, or IL-17RE) to transduce signals from multiple IL-17 family ligands (IL-17A, IL-17F, IL-17A/F, IL-17B, IL-17C, IL-17E/IL-25); upon cytokine binding, IL-17RA dimerizes to form a 2:2:2 hexameric signalosome, and its extended SEFIR/TILL intracellular domain recruits Act1 via CC'-loop interactions to activate TRAF6 ubiquitination, NF-κB, and MAPK (ERK, p38, JNK) pathways, driving expression of chemokines (CXCL1/2/5/8, CCL20), inflammatory cytokines (IL-6), and matrix metalloproteases; additional context-specific signaling includes JAK2/STAT3 in fibroblasts, Rab35/PKCα in airway smooth muscle, Syk in macrophages, and ATOH1 induction in intestinal stem cells; natural loss-of-function mutations in humans abolish responses to IL-17A/F and IL-25, causing chronic mucocutaneous candidiasis and staphylococcal infections, establishing its non-redundant role in mucocutaneous immunity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL17RA is a shared receptor subunit that nucleates signaling for multiple IL-17 family cytokines by pairing with distinct co-receptors—IL-17RC for IL-17A, IL-17F, and the IL-17A/F heterodimer [#0, #4], IL-17RB for IL-25/IL-17E and IL-17B [#1, #36], and IL-17RE for IL-17C [#30, #37]. Cytokine binding drives IL-17RA dimerization and assembly of a 2:2:2 hexameric IL-17RA/IL-17RC/IL-17A signalosome, and dimerization-defective IL-17RA mutants lose downstream gene induction [#9]; structural studies of IL-17RC bound to IL-17F reveal a competing 2:1 cytokine-binding geometry [#8]. Signal transduction requires an extended SEFIR+TILL intracellular module whose CC' loop directly binds the adaptor Act1, an interaction necessary for TRAF6 ubiquitination and downstream output [#2, #3], with RKIP acting as a positive scaffold that stabilizes the IL-17RA–Act1 complex [#7]. Engagement activates NF-\\u03baB, AP-1, and the ERK/p38/JNK MAPK cascades to drive chemokine and cytokine programs (IL-6, IL-8, CCL20, ELR+ CXC chemokines, MMPs) [#4, #5, #6], with context-specific use of STAT3/JAK2 in fibroblasts [#21, #27], Rab35/PKC\\u03b1-fascin in airway smooth muscle [#17], and Syk in macrophages [#29]. Through these pathways IL17RA governs barrier and tissue physiology, including neutrophil recruitment to lung [#14, #23], intestinal secretory-lineage commitment via ATOH1 [#16], control of microbiota and gut-liver immunity [#20], and tumor-suppressive epithelial and macrophage functions in colorectal cancer [#29]. Complete autosomal recessive IL17RA deficiency in humans abolishes responses to IL-17A/F and IL-25 and causes chronic mucocutaneous candidiasis and staphylococcal infection, establishing its non-redundant role in mucocutaneous immunity [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that IL17RA is not a solitary receptor but functions in obligate heteromeric complexes with co-receptors to read distinct IL-17 family ligands.\",\n      \"evidence\": \"siRNA knockdown plus SPR binding for IL-17A/F via IL-17RA/IL-17RC, and KO mice plus blocking antibody for IL-25 via IL-17RA/IL-17RB\",\n      \"pmids\": [\"18684971\", \"18768888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the assembled complexes not resolved\", \"Mechanism coupling ligand binding to intracellular signaling not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the molecular basis of intracellular signal initiation by mapping the Act1-binding determinant to the CC' loop of an extended SEFIR+TILL domain, distinguishing receptor engagement from downstream output.\",\n      \"evidence\": \"Structure-function deletion mutagenesis, SPR with CC' loop peptide, and a cell-permeable decoy peptide blocking signaling in vitro and in vivo\",\n      \"pmids\": [\"20729198\", \"22045852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the SEFIR-SEFIR interface not determined\", \"How TRAF6 ubiquitination is mechanistically licensed downstream of Act1 not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed that the IL17RA/IL-17RC pair converges on NF-\\u03baB, AP-1, and ERK/p38/JNK MAPK to drive chemokine and inflammatory cytokine programs across epithelial and stromal cell types.\",\n      \"evidence\": \"siRNA knockdown of either receptor with MAPK Western blotting, transcription factor activation assays, ELISA, and microarray in synoviocytes, gastric cells, and airway smooth muscle\",\n      \"pmids\": [\"17644350\", \"21109515\", \"18097068\", \"15893694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of each MAPK branch to specific gene targets not dissected\", \"Cell-type determinants of pathway selection unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the architecture of the signaling-competent receptor, revealing ligand-induced IL17RA dimerization into a 2:2:2 hexamer and an alternative IL-17RC-centered 2:1 geometry, linking assembly to function.\",\n      \"evidence\": \"X-ray crystallography of IL-17RA/IL-17RC ectodomains with IL-17A/IL-17F, biophysical binding, and dimerization-defective mutants tested in keratinocytes\",\n      \"pmids\": [\"32187518\", \"36260993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-17RA-independent IL-17RC signaling occurs in cells not directly demonstrated\", \"Conformational coupling from ectodomain assembly to intracellular SEFIR not visualized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified positive and small-molecule modulators of the IL17RA–Act1 axis, expanding the regulatory and pharmacological control points of the receptor.\",\n      \"evidence\": \"Co-IP and KO/EAE for RKIP as a scaffold; structure-based and SPR/pull-down identification of cyanidin, HAP peptide, and gingerenone A blocking the IL-17A/IL17RA interface\",\n      \"pmids\": [\"29674348\", \"28223414\", \"27184415\", \"38639442\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous regulation of RKIP-IL17RA coupling in human disease not established\", \"Inhibitor specificity versus other IL-17 family receptors not fully delineated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed cell-type-specific, non-canonical IL17RA signaling outputs beyond NF-\\u03baB/MAPK, including cytoskeletal, metabolic, and differentiation programs.\",\n      \"evidence\": \"Conditional KO and co-IP for Rab35/PKC\\u03b1-fascin in airway smooth muscle, STAT3/JAK2 axes in fibroblasts, STAT3/FABP4 in ovarian cancer, and ATOH1 induction in intestinal stem cells/organoids\",\n      \"pmids\": [\"30683702\", \"30604628\", \"31802182\", \"35081371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single receptor selects among these divergent outputs is unresolved\", \"Direct biochemical links from IL17RA to JAK2/STAT3 not fully mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated tissue-protective and barrier functions of IL17RA in epithelial and stromal compartments, including microbiota control, gut-liver immunity, and tumor suppression.\",\n      \"evidence\": \"Tissue-specific conditional KO with 16S sequencing, hepatitis and colorectal tumor models, Syk activation assays, and bacterial/viral challenge models\",\n      \"pmids\": [\"31747600\", \"29760692\", \"40023157\", \"19783685\", \"26871571\", \"34516780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compartment-specific signaling mechanisms not uniformly defined\", \"Translation of protective epithelial roles to human disease incompletely characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established the non-redundant human in vivo function of IL17RA by showing that biallelic loss-of-function abolishes responses to IL-17A/F and IL-25 and causes mucocutaneous infection susceptibility.\",\n      \"evidence\": \"Genetic analysis of 21 patients with surface expression flow cytometry and functional IL-17 response assays in fibroblasts and leukocytes\",\n      \"pmids\": [\"27930337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype variation across alleles not fully explained\", \"Contribution of individual ligand pathways to specific clinical features not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-transcriptional and isoform-level regulation of IL17RA abundance as a control point in chronic inflammation.\",\n      \"evidence\": \"MeRIP-seq with FTO knockdown/overexpression in liver injury models, and RT-PCR/Western detection of a soluble splice isoform lacking the transmembrane domain\",\n      \"pmids\": [\"36172147\", \"24084331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of the soluble isoform (decoy vs. agonist) not tested\", \"Physiological triggers of FTO-mediated IL17RA regulation unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single shared receptor subunit selects among NF-\\u03baB/MAPK, STAT3, cytoskeletal, and differentiation outputs in a cell-type- and ligand-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking co-receptor identity to downstream pathway choice\", \"Structural basis of intracellular signalosome assembly in cells not determined\", \"Function of the soluble IL17RA isoform unestablished\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 9, 26]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 36, 37]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 25, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 14, 26, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 29]}\n    ],\n    \"complexes\": [\n      \"IL-17RA/IL-17RC receptor complex\",\n      \"IL-17RA/IL-17RB receptor complex\",\n      \"IL-17RA/IL-17RE receptor complex\",\n      \"IL-17R-Act1 signaling complex\"\n    ],\n    \"partners\": [\n      \"IL17RC\",\n      \"IL17RB\",\n      \"IL17RE\",\n      \"TRAF3IP2\",\n      \"TRAF6\",\n      \"PEBP1\",\n      \"RAB35\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}